The solubility in water of many lipophilic compounds may be increased through the formation of inclusion complexes with cyclodextrins and their derivatives. Szejtli in Cyclodextrin Technology (pp. 186-306) gives many examples of the uses of such solubilization in pharmaceuticals. In a majority of the described pharmaceutical applications underivatized cyclodextrins, which are crystalline, or crystalline derivatives thereof are utilized to increase the water solubility of lipophilic compounds. However, improvements in solubility could also be obtained when amorphous derivatives of cyclodextrins were used instead of crystalline derivatives (e.g., hydroxypropylcyclodextrins). (J. Pitha, U.S. Pat. No. 4,727,064; B. W. Muller, U.S. Pat. No. 4,764,604).
Complexes of cyclodextrins and their crystalline derivatives with lipophiles have often been prepared by co-dissolution of components in water (Szejtli, 1.c., pp. 80-90). In some instances (e.g., vitamin D.sub.3, Szejtli, 1.c., pp. 85 and 268) addition of an organic solvent (ethanol, acetone) was necessary, but such solvents could be used only sparingly since they precipitated the cyclodextrins utilized. Today, when such cyclodextrin complexes are prepared on a technical scale, a solid phase method of preparation (kneading of components) is the method of choice.
Improvements in the pharmaceutical usefulness of peptides by using hydroxypropylcyclodextrin was studied by Hora et al. The studied peptides included several hormones and peptidic factors; no co-solvent was used in the study (Hora et al, Int. Applic. No. PCT US 89 04099).
The preparation of the amorphous hydroxypropylcyclodextrin complexes has usually required prolonged stirring of components in water (J. Pitha, U.S. Pat. No. 4,727,064 and B. W. Muller, U.S. Pat. No. 4,764,604). In contrast to cyclodextrins, hydroxypropylcyclodextrins are quite soluble in polar organic solvents, including 190 proof U.S. Pharmacopeia ethanol (J. Pitha et al., Int. J. Pharm. 29, 73-82, 1986). Nevertheless, the addition of organic solvents at such solubilizing concentrations has not been used in the preparation of such complexes, since there has been the additional concern that nearly all solvents form complexes with cyclodextrins, and thus solvent molecules may displace the solubilized lipophile from formed inclusion complexes. In this regard, Table 1 contains data on reported stability constants of complexes of solvents with .alpha.- and .beta.-cyclodextrin.
Ammonia has previously been used as a co-solubilizer in the preparation of complexes of crystalline cyclodextrins with non-steroidal antiinflammatory drugs (K. Kurozumi et al., Chem. Pharm. Bull. 23, 3062-3068, 1975). Ammonia was also used as a co-solubilizer in the preparation of pancratistatin:hydroxypropyl-.beta.-cyclodextrin complex (J. Torres-Labandeira, P. Davignon, and J. Pitha, J. Pharm. Sci., accepted for publication, June 1990). Ammonia forms a quite stable complex with cyclodextrins (Table 1).
Concerning macrocyclic antibiotics, the first example studied was polymyxin, which was found to form complexes with .beta.-cyclodextrin derivatives (Cserkali et al., J. Chromatoor. 259, 107-110, 1983). Another antibiotic of this type, amphotericin B, was the subject of U.S. Pat. No. 4,883,785 of Chow et al.; these inventors disclosed that amphotericin B can be solubilized by the addition of the drug to an alkaline solution of cyclodextrins, preferably .gamma., followed by neutralization of the solution. Complexes of amphotericin B with underivatized cyclodextrins were also the subject of a publication by Vikmon et al. (J. Antibiot. 38, 1822-1824, 1985) and by Rajagopalan et al. (Int. J. Pharm. 29, 161-168, 1986). U.S. patent application, Ser. No. 07/345,928 by Anaissie et al. addressed the solubilization of amphotericin B and other macrocyclic antibiotics by hydroxypropylcyclodextrins, but no cosolvent was used in the preparations described there.
TABLE 1 ______________________________________ Stability constants (M.sup.-1) of the complexes of solvents with .alpha.- and .beta.-cyclodextrin Solvent .alpha.-cyclodextrin .beta.-cyclodextrin ______________________________________ methanol 1(b) 1(a) ethanol 5(a) 6(b) 4.8(c) 1(a) 1(b) n-propanol 20(a) 23(b) 5(a) 4(b) 2-propanol 3(a) 5(b) 4.6(c) 2(a) 4(b) n-butanol 110(a) 89(b) 15(a) 17(b) t-butanol 2(a) 4(b) 4.1(c) 42(a) 48(b) n-pentanol 300(a) 323(b) 87(a) 63(b) 2,2-dimethyl-1- 30(a) 660(a) 580(b) propanol ammonia 61000(d) 15000(d) dimethyl sulf- 0.4(c) oxide dioxane 4.4(c) ______________________________________ (a)taken from M. Suzuki et al., Chem. Pharm. Bull. 36, 720-725, 1988; (b)taken from Y. Matsui and K. Mochida, Bull. Chem. Soc. Japan 52, 2808-2814, 1979; (c)taken from R. I. Gelb et al., J. Am. Chem. Soc. 104, 6283-6288, 1982; (d)taken from W. Hirsch et al., Can. J. Chem. 65, 2661-2664, 1987.